Summary of Work: Aneuploidy is the most common constitutive chromosomal abnormality in humans. Most aneuploidy in humans is considered to be of germ cell origin, arising from errors in maternal or paternal meiotic chromosomal segregation. Methodology for a three chromosome (X, Y and 8) sperm-FISH assay in the mouse and a two-chromosome (Y and 4) sperm-FISH assay in the rat has been developed at Lawrence Livermore National Laboratory (LLNL) under an NIEHS-DOE Interagency agreement. We are participating in the evaluation of these methods through conduct of positive control experiments. The animal assays that are being developed under this project serve as parallel models to a human sperm-FISH assay previously developed by our collaborators at LLNL and will be used to evaluate the aneugenic potential of environmental chemicals tested in NTP bioassays and answer critical questions regarding the mechanisms of aneuploidy induction which cannot be addressed in human studies.Last year, results of our aneuploidy studies on sperm-FISH slides prepared from male mice treated at NIEHS (TB 92-01) with single i.v. injections of either Novantrone (N), Oncovin (o) or Vinblastine (V) were negative. This past year, we completed a study involving a combination of all three chemicals at their mid- or high-dose levels plus Prednisone (P), using a regimen which modeled a similar study of aneuploidy in human sperm obtained from Hodgkin's patients. These results were positive. Unexpectedly, the highest response was obtained was with sperm from a "control" mouse given only Prednisone. We are curently designing a repeat study which will involve a combination of the low-doses of NOV (the mg/m2 human-equivalent doses) plus P. Additional P 'controls' will also be included. A study to determine the base-line frequencies of hyperhaploidy for chromosomes Y and 4 in 3 strains of rats (F344, SD and Wistar) was also conducted.